P1403: SI101-01 PHASE I/II STUDY EVALUATING SAFETY AND EFFICACY OF ALLOGENEIC SMART101 T-LYMPHOID PROGENITOR INJECTION TO ACCELERATE IMMUNE RECONSTITUTION AFTER T-CELL DEPLETED ALLOGENEIC HSCT
Authors: Jaap Jan Boelens, Muhammad Umair Mushtaq, Joseph Mcguirk, Aurelie Bauquet, Laura Simons, Pierre Heimendinger, Pierre Gaudeaux, Isabelle Andre, Juliette Paillet, Olivier Negre, Tayebeh-Shabi Soheili, Sebastien Oster, Marcel R.M. van den Brink, Frederic Lehmann, Marina Cavazzana, Miguel-Angel Perales
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for several patients (pts) with hematological malignancies. Reconstitution of a T cell compartment may take up to 2 years, although it is of key importance in the defense against pathogens and as a mediator of graft versus tumor immune response. T-cell depletion (TCD) allo-HSCT by in vivo graft manipulation with anti-thymocyte globulin (ATG) and ex vivo graft CD34+ selection are strategies used to reduce the risk of GvHD without increased relapse or decreased survival. But immune recovery after TCD allo-HSCT is slow due to the scarcity of T-cells administered in the graft. SMART101 is a cellular therapy using CD34-CD7+ T-lymphoid progenitors produced in culture from mobilized peripheral blood CD34+ cells of the transplant donor via Smart Immune’s ProTcell platform. This GMP ex-vivo lymphoid niche culture system, using Notch ligand Delta-like 4 coupled to IgG2 Fc fragment (DLL4-Fc) and RetroNectin® in the presence of a specific cytokines, mimics the initial steps of bone marrow lymphoid and T-cell differentiation. According to preclinical data, SMART101 cells infused into a pt should complete their differentiation directly in the thymus with positive and negative TCR selection, leading to the generation of a polyclonal repertoire of educated naïve T-cells faster than an allograft with hematopoietic stem cell alone. Aims: The SI101-01 clinical study seeks to provide proof of principle that SMART101 cells can rapidly complete their differentiation in the thymus into naïve T-cells giving rise to long-lasting polyclonal donor T-cells without GvHD-inducing potential to reduce the non-relapse and disease relapse mortality post TCD allo-HSCT. Methods: This Phase I/II study (NCT04959903) evaluates the safety and efficacy of SMART101 infused between D4-D10 post-TCD allo-HSCT in adult (match related or unrelated donor [MUD]) and pediatric (MUD) pts with AML, ALL or high-risk MDS. It is a dose-escalation study evaluating 2 dose levels (DL) of SMART101 (0.75 and 1.5 x 106 CD7+ cells/kg) with 12 pts at the recommended dose. Pts receive a TCD allo-HSCT following myeloablative conditioning with upfront ATG administration. The co-primary endpoints of the trial are (i) the occurrence of unacceptable toxicity and acute GvHD; (ii) the immune reconstitution efficacy defined by CD4+ T cells count ≥ 50/μL by D100. Secondary endpoints evaluate the overall safety profile and non-relapse/relapse mortality. Results: Fig 1 shows SMART101 cells characterization by single cell RNAseq. Most of the cells express CD7 and about half of them are CD161+, both being lymphoid markers. In contrast, they do not express CD34 and not yet CD1a, confirming their early stage on T-cell differentiation. Regarding the molecules involved in the migration of progenitors into the thymus, most of the cells are positive for chemokine receptor CXCR4 and for SELL, coding for L-selectin, an adhesion molecule. CCR9, a chemokine receptor mediating chemotaxis to the thymus and SELPLG coding for PSGL-1a glycoprotein important for cell trafficking are also expressed in a smaller fraction of the cells. As of February 23, 1 patient was enrolled at DL-I. SMART101 was well tolerated, with no aGvHD after 8 weeks with engraftment at D11 post-transplant. The study design, preliminary safety and clinical data from the first DL as well as details of the ProTcell platform will be presented at the EHA 2023. Summary/Conclusion: SMART101 is the first-generation of allogeneic T lymphoid progenitor cells obtained through Smart Immune’s ProTcell platform, the first scalable progenitor T-cell manufacturing system in clinics. The early data indicate that SMART101 is well tolerated with a good safety profile.Keywords: Thymic function, Post-transplant, CD4+ T cells, Allogeneic hematopoietic stem cell transplant